Menopause is a condition in women wherein their bodies no longer produce estrogen and is responsible for physical and physiological changes in the body including bone loss, osteoporosis, cardiovascular disease, senile dementia/Alzheimer's disease, flushing (hot flashes), urogenital atrophy, dysmenorrhea and acne. Decreased production of estrogen, whether from normal onset of menopause or surgically induced menopause through the removal of the ovaries, is also associated with impaired cognitive function, particularly memory and attention loss, and neurodegeneration.
Estrogen loss has also been correlated with decreased acetylcholine uptake (Simpkins J. W. et al., Neurobiology of Aging, 1994, 15 Suppl. 2, 5195-5197). Acetylcholine is a neurotransmitter found in cholinergic synapses in neuromuscular junctions and in the central nervous system.
In the nervous system, a nerve impulse is transmitted as an electrical signal along a neuron until it reaches the neuron ending. The nerve ending contains vesicles filled with acetylcholine. The nerve impulse stimulates the vesicles to release acetylcholine into the synapse through the pores in the pre-synapse membrane. The acetylcholine diffuses through the synapse gap very quickly (within 1 millisecond) and reaches the post-synapse membrane. The acetylcholine depolarizes the post-synapse membrane, generating an electrical impulse.
The passage of an impulse through the synapse is brief and unidirectional. Once acetylcholine has conveyed the nerve impulse across the synapse, the acetylcholine must be cleared from the gap so that polarization of the post-synaptic membrane can be restored, and the next impulse can be transmitted. Acetylcholinesterase, or simply cholinesterase, found at post-synaptic gaps, hydrolyzes acetylcholine to choline and acetic acid (“acetylcholine uptake”). Estrogen-deficient women, menopausal or post-menopausal, may suffer from increased memory loss and general neurodegeneration due to the effect of low estrogen levels on acetylcholine uptake.
Estrogen-deficient women may also suffer from muscle fatigue. With respect to neuromuscular function, after continuous or repetitive movement or exercise, fatigue reduces the strength and duration of the impulses generated, and the amount of acetylcholine released by the pre-synapse membrane decreases. As a result of these factors, the energy level of the muscle cell is decreased and the excitation threshold becomes more difficult to overcome. Maintenance of motor functions depends on the body's ability to successfully transmit a nerve impulse and stimulate muscle fibers for muscle contraction. A decrease in effective nerve impulse transmissions leads to degeneration of motor function manifested by fatigue and loss in coordination. Although the function of the neuromuscular system is influenced by temporary factors such as stress level and food intake, and long-term factors such as age, genetics, general fitness and nutrition levels, hormone serum levels play a prodigious role in maintaining normal motor function. For example, estrogen deficiency intensifies the effects of impaired neuromuscular connections by further decreasing energy levels of muscle cells due to diminished acetylcholine uptake. The loss of coordination is especially disadvantageous in estrogen-deficient women who may have osteoporosis, as they are more susceptible to the effects of falls, i.e., bone damage.
Acetylcholinesterase inhibitors enhance the effects of acetycholine, either by inhibiting its hydrolyzation or increasing the time the acetylcholine is present in the synapse. Galanthamine is a known acetylcholinesterase inhibitor. Galanthamine reversibly binds to acetylcholinesterase, inhibiting its action and resulting in an increase in local concentrations of acetylcholine. Galanthamine has been used in the treatment of different diseases of the nervous system such as Alzheimer's disease (U.S. Pat. No. 5,958,903) and Parkinson's disease (U.S. Pat. No. 5,965,571); the treatment of chronic fatigue syndrome (U.S. Pat. No. 5,312,817); as an erectogenic agent in the treatment of male sexual dysfunction (U.S. Pat. No. 5,177,070) as well as the treatment of glaucoma, myasthenia gravis and senile dementia.
Galanthamine is typically used in pharmaceutical compositions in purified form and is obtained by complex chemical extractions from plant sources (U.S. Pat. No. 5,877,172) or chemically synthesized (U.S. Pat. Nos. 5,777,108 and 5,958,903). These processes may be disadvantageous in that they utilize undesirable chemicals such as chlorohydrocarbons and involve purification processes forming galanthamine salts.
A variety of hormone replacement therapies are presently available to help alleviate the deleterious physical and physiological changes associated with menopause. Such regimens include combination therapies using estradiol and conjugated equine estrogens such as Premarin® (sodium 13-methyl-17-oxo-3-sulfonatooxy-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a] phenanthrene) (Wyeth-Ayerst Laboratories, Princeton, N.J.). Hormone replacement therapies provide benefits in the areas of cardiovascular disease and bone loss, however have numerous side effects including endometrial cancer, increased risk of breast cancer, and vaginal and uterine bleeding. Single agent hormone replacement therapy using the steroidal compound 17 alpha-dihydroequilenin has been disclosed to prevent neurodegeneration associated with cognitive dysfunction in estrogen deficient conditions including menopause (U.S. Pat. No. 5,719,137).
Thus, estrogen replacement therapy is used to treat women with estrogen deficiency to alleviate the deleterious physical and physiological symptoms associated with menopause. However, hormone replacement therapy may not be desirable for treating women who have had cancer or are at a high risk for cancer, especially breast cancer and uterine cancer. Some women for whom hormone replacement therapy is suitable may seek to supplement or enhance these therapies for additional physical or physiological benefits. Other women may be averse to taking hormone therapies. Therefore, alternative treatments for these women for ameliorating deleterious effects of estrogen loss that are free of the potential risks associated with hormone replacement therapy are highly desirable.
An herbal preparation containing a natural form of an acetylcholinesterase inhibitor which can be used to improve loss in cognitive function in estrogen deficient women has heretofore not been disclosed.